Design and synthesis of dual-active heterocyclic yybrid inhibitors for β-Hematin and plasmodium falciparum N-Myristoyltransferase

Hay, Jonathan Bruce (2016-03)

Thesis (MSc)--Stellenbosch University, 2016.

Thesis

ENGLISH ABSTRACT: The current project focused on the design and synthesis of a novel antiplasmodial dual-active conjugate hybrid compound based on an indole scaffold and known antiplasmodial quinolines. The two scaffolds were chosen to target independent pathways in the malaria parasite, namely N-myristoylation and hemozoin formation. Initially, a novel indole compound, ethyl 4-(piperidin-4-yloxy)-1H-indole-2-carboxylate, which would possibly function as a Plasmodium N-myristoylation inhibitor, was synthesised. This would also function as the precursor to the proposed hybrid compound. The synthetic methodology that was employed included the synthesis of starting materials, 2-(benzyloxy)benzaldehyde and ethyl 2-azidoacetate, utilizing well-known benzyl protection and substitution reactions. These compounds were condensed into an azide cinnamate, (Z)-ethyl 2-azido-3-[2-(benzyloxy)phenyl]acrylate, via the Knoevenagel condensation reaction. An alternative method was investigated to obtain the same azide compound via an Arbuzov ylide formation and Horner-Wadsworth-Emmons Wittig-type reaction to obtain an E-stereospecific cinnamate, (E)-ethyl 3-[2-(benzyloxy)phenyl]acrylate, followed by a cerium ammonium nitrate mediated azide addition to afford the azide cinnamate. The azide cinnamate was later subjected to a Hemmetsberger thermal cyclization to form the indole scaffold, ethyl 4-(benzyloxy)-1H-indole-2-carboxylate, followed by a Mitsunobu reaction to afford the novel indole compound. Saponification yielded the carboxylic acid indole derivative, 4-(benzyloxy)-1H-indole-2-carboxylic acid, which was to function as a precursor to the hybrid compound, since an amidation reaction was considered as a possible method for coupling the indole and quinoline scaffolds. Later, 4,7-disubstituted quinoline derivatives were targeted as these would function as the second heterocyclic scaffold for the intended hybrid compound. These were synthesized according to the Gould-Jacobs, Skraup and Doebner-Miller methods, using simple m-substituted anilines as starting materials. The Gould-Jacobs reaction provided the desired 4-chloro-7-substituted quinolines (7-Br, -F, -NO2, -CH3and -OCH3), however, the Skraup and Doebner-Miller reactions only provided the 7-substituted quinolines (7-Br, -CH3 and -OCH3) and required the use of a subsequent oxidation reaction to yield quinoline N-oxides that were later chlorinated to give the desired 4-chloro-7-substituted quinolines. Following the synthesis of the desired quinoline substructures, the 4-chloro-7-substituted quinolines were converted to the desired quinoline pendant groups, N1-7-X-quinolin-4-yl)ethane-1,2-diamine (X = CF3 and Cl), via a chloride substitution reaction using diamino ethane. Preliminary investigations were carried out to obtain the proposed hybrid compound and to ascertain whether an amidation reaction was suitable for the coupling of the two heterocyclic scaffolds. Given time constraints towards the end of the project, only an N, N′-carbonyldiimidazole (CDI) facilitated amidation was investigated. Unfortunately, the approach was not successful. The challenge remains therefore, to utilize the methodologies optimized in this project to investigate heterocyclic hybrid compounds as novel resistance reversers in the treatment of malaria.

AFRIKAANSE OPSOMMING: Die huidige projek het gefokus op die ontwerp en sintese van 'n nuwe, unieke antiplasmodiale, dubbel geaktiveerde hibriedverbinding wat as uitgangspunt op 'n indoolbasis en bekende antiplasmodiale kinoliene gerig is. Twee weë is gekies om onafhanklike roetes in die malaria-parasiet, naamlik N-miristoïelisasie en hemosoïenvorming, te teiken. Aanvanklik was 'n nuwe indool-verbinding, gesintetiseer, etiel 4- (piperidien-4-ieloksi)-1H-indool-2-karboksilaat, wat moontlik sou kon funksioneer as 'n Plasmodium N-myristoylation inhibeerder. Dit sou ook kon dien as die uitgangsverbinding tot die voorgestelde hibriedverbinding. Die sintese metodiek wat in gebruik was, was onder meer, die sintese van die uitgangsverbindings, 2-(bensieloksi) bensaldehied en etiel 2-asidoasetaat, deur die gebruik van bekende bensiel-beskerming en substitusie-reaksies. Hierdie verbindings was verander na ‘n asiedsinnamaat, (Z)-etiel-2-asido-3-[2-(bensieloksi)feniel]akrilaat, deur die Knoevenagel kondensasie-reaksie. 'n Alternatiewe metode was ook ondersoek om dieselfde asiedverbinding te verkry deur 'n Arbuzov iliedvormings reaksie en’n Horner-Wadsworth-Emmons-Wittig-tipe reaksie om 'n E-stereospesifieke sinnamaat te verkry, (E)-etiel 3-[2-(bensieloksi)feniel]akrilaat , gevolg deur 'n serium-ammoniumnitraat bemiddelde asied byvoeging om die asiedsinnamaat te verkry. Om die gewenste indool bousteen te berei en dan die nuwe unieke indoolverbinding te verkry, was die asiedsinnamaat onderworpe aan 'n Hemmetsberger termiese siklisasie om etiel 4-(bensieloksi)-1H-indool-2-karboksilaat te verkry en gevolg deur 'n Mitsunobu-reaksie. Verseeping lewer die karboksielsuur-indool-afgeleide, 4-(bensieloksie)-1H-indool-2-karboksielsuur.Hierdie verbinding sou as 'n voorloper dien vir die sintese van die hibriedverbinding aangesien 'n amidasie-reaksie as 'n moontlike koppelings metode vir die indool- en kinolien-boustene, om die hibriedverbinding te vorm, oorweeg was. Later was 4,7-digesubstiteerde kinolien-afgeleides gebruik omdat dit as die tweede heterosikliese bousteen sou kon funksioneer vir die beoogde hibriedverbinding. Hierdie verbindings was gesintetiseer volgens die Gould-Jacobs, Skraup en Doebner-Miller metodes, deur die gebruik van eenvoudige m-gesubstiteerde aniliene as uitgangsverbindings. Die Gould-Jacobs reaksie het die gewenste 4-chloor-7-gesubstiteerde kienoliene (7-Br, -F, -NO2, -CH3 en -OCH3) gelewer. Die Skraup en Doebner-Miller reaksies het slegs die 7-gesubstiteerde kinoliene ( 7-Br, -CH3 en -OCH3) gelewer en het die gebruik van 'n daaropvolgende oksidasie-reaksie vereis om kinolien N-oksiede te berei, wat later gechlorineer was om die verlangde 4-chloor-7-gesubstiteerde kinoliene te gee. Na aanleiding van die sintese van die vereiste kinolien-substrukture, was die 4-chloor-7-gesubstiteerde kinoliene omgeskakel na die gewenste kinolien sygroepe, N1-7-X-(kinolien-4-iel)etaan-1,2-diamien (X = CF3 en Cl), deur 'n chloried gesubstitusie-reaksie met behulp diaminoetaan.

Please refer to this item in SUNScholar by using the following persistent URL: http://hdl.handle.net/10019.1/98291
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